1. Field of the Invention
This invention pertains generally to synthesis schemes and methods for producing small organic molecules, and more particularly to compositions and methods for producing libraries of structurally and stereochemically diverse heterocyclic compounds with distinct scaffolds and functional molecules that can be screened for biological or chemical activity. Several molecules that were shown to inhibit human breast cancer cell migration were identified from one functional analysis of the library.
2. Description of Related Art
The relationship between the structure and function of interacting molecules is a fundamental issue in the study of biological and other chemistry-based systems. For example, structure-function relationships are important in understanding the function of enzymes, cellular communication, cellular control and feedback mechanisms, and the biological activity of pharmaceutical agents.
Certain macromolecules are known to interact and bind to other molecules that have a specific 3-dimensional spatial and electronic distribution resulting in predictable biological or chemical activity. The identification of structures and molecular interactions are important in the development of pharmacological or therapeutic agents that are useful in human or animal health care, agriculturally useful chemicals, selective biocides for insects, weeds, or other pests, as well as catalytic and other entities useful in a variety of industrial processes.
Drug discovery has evolved from essentially random screening of natural products into a scientific process that not only includes the rational and combinatorial design of large numbers of synthetic molecules as potential bioactive or chemical agents but also includes the mechanistic and structural characterization of their biological targets.
However, there are significant hurdles to overcome in order to predict a desired function based on structure alone as well as in the identification and design of high affinity ligands for a particular biological target of interest. These hurdles include the difficulty in defining rules for predicting whether a particular small molecule will interact with proteins along with the task of elucidating the structure of ligands and targets and the nature of their interactions.
Another hurdle is the large number of compounds that need to be generated in order to identify and evaluate new leads or to optimize existing leads. The structural similarities and dissimilarities between these large numbers of compounds need to be identified and the structural features need to be correlated with the activity and binding affinity, because small structural changes can lead to large effects on the overall biological activities of compounds.
One approach toward broadening the understanding of the relationship between structure and function is to generate many new small molecules that potentially modulate the functions of a particular protein and to study the interactions between them. In this context, collections of compound libraries can be established as common starting points for the study of chemical genetics and the discovery of new drugs. The strategy of small compound discovery has moved from the selection of drug leads from among compounds that are individually synthesized and tested to the creation and screening of large collections of compounds. These collections may be from natural sources or generated by synthetic methods such as combinatorial chemistry. These collections of compounds may be generated as libraries of individual, well-characterized compounds synthesized, e.g., via high throughput, parallel synthesis or as a mixture or a pool of up to several hundred or even several thousand molecules synthesized by split-mix or other combinatorial methods.
The development of efficient methods for the construction of libraries encompassing the maximum amount of chemical space is a particularly challenging task for organic chemists. Establishing the maximum amount of skeletal diversity is a key factor toward improving the screening efficiency for novel therapeutic leads. Diversity-oriented synthesis (DOS) entails the development of pathways leading to the efficient synthesis of collections of small molecules exhibiting rich skeletal and stereochemical diversity.
Compared with libraries constructed from common scaffolds decorated with diverse substituents, there are very few examples of libraries of small molecules featuring high degrees of skeletal and stereochemical diversity. In addition, although such exercises are undertaken based on the premise that a diverse range of scaffolds should provide a higher chance for discovery of small-molecule biological functional modulators, its actual realization is rarely reported.
The identification of ligands that bind may provide a lead for identifying compounds with a desired biological activity, e.g., as a potential drug candidate. As methods have become available to screen these complex mixtures more effectively, interest in exploiting the “rational design” or the “directed molecular evolution” approaches have increased.
Accordingly, there is a need for a system and method for reliably and efficiently producing libraries of molecules with significant skeletal and stereochemical diversity that can be screened for chemical and biological activity. The present invention satisfies these needs as well as others and is generally an improvement over the art.